neurogenetics

, Volume 11, Issue 1, pp 81–89 | Cite as

Disruption of CNTNAP2 and additional structural genome changes in a boy with speech delay and autism spectrum disorder

  • Martin Poot
  • Vera Beyer
  • Ira Schwaab
  • Natalja Damatova
  • Ruben van’t Slot
  • Jo Prothero
  • Sue E. Holder
  • Thomas Haaf
ORIGINAL ARTICLE

Abstract

Patients with autism spectrum disorder (ASD) frequently harbour chromosome rearrangements and segmental aneuploidies, which allow us to identify candidate genes. In a boy with mild facial dysmorphisms, speech delay and ASD, we reconstructed by karyotyping, FISH and SNP array-based segmental aneuploidy profiling a highly complex chromosomal rearrangement involving at least three breaks in chromosome 1 and seven breaks in chromosome 7. Chromosome banding revealed an inversion of region 7q32.1–7q35 on the derivative chromosome 7. FISH with region-specific BACs mapped both inversion breakpoints and revealed additional breaks and structural changes in the CNTNAP2 gene. Two gene segments were transposed and inserted into the 1q31.2 region, while the CNTNAP2 segment between the two transposed parts as well as intron 13 to the 5-UTR were retained on the der(7). SNP array analysis revealed an additional de novo deletion encompassing the distal part of intron1 and exon 2 of CNTNAP2, which contains FOXP2 binding sites. Second, we found another de novo deletion on chromosome 1q41, containing 15 annotated genes, including KCTD3 and USH2A. Disruptions of the CNTNAP2 gene have been associated with ASD and with Gilles de la Tourette syndrome (GTS). Comparison of disruptions of CNTNAP2 in patients with GTS and ASD suggests that large proximal disruptions result in either GTS or ASD, while relatively small distal disruptions may be phenotypically neutral. For full-blown ASD to develop, a proximal disruption of CNTNAP2 may have to occur concomitantly with additional genome mutations such as hemizygous deletions of the KCTD3 and USH2A genes.

Keywords

Autism Speech delay Insertion translocation CNTNAP2 gene KCTD3 gene USH2A gene 

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Martin Poot
    • 1
  • Vera Beyer
    • 2
  • Ira Schwaab
    • 2
  • Natalja Damatova
    • 2
  • Ruben van’t Slot
    • 1
  • Jo Prothero
    • 3
  • Sue E. Holder
    • 3
  • Thomas Haaf
    • 2
  1. 1.Department of Medical GeneticsUniversity Medical Centre UtrechtUtrechtThe Netherlands
  2. 2.Institute of Human GeneticsJohannes Gutenberg University MainzMainzGermany
  3. 3.North West Thames Regional Genetics ServiceNWLH NHS TrustHarrowUK

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